Spectrum and Clinical Impact of Secondary Genetic Alterations in Translocation-Associated Sarcomas

Translocation-associated sarcomas (TASs) encompass a wide spectrum of pathologic entities and clinical behavior. Driven by the oncogenic fusion, TASs typically show a stable genome and a low tumor mutational burden (TMB), with infrequent secondary genetic alterations (SGAs). Although oncogenic/likely oncogenic SGAs have been associated with an aggressive clinical course in certain histotypes, a comprehensive comparative study of their clinical impact across TAS histotypes has not been performed to date.

Herein, we investigate the genomic landscape of 632 TASs, spanning the most common histotypes: Ewing sarcoma (ES, n = 196), desmoplastic small round cell sarcoma (DSRCT, n = 115), solitary fibrous tumor (SFT, n = 87), synovial sarcoma (SS, n = 75), etc. All tumors were tested on a clinically validated, matched tumor-normal DNA-targeted next-generation sequencing panel, with confirmed gene fusion partners. Both gene-level and arm-level copy number alterations were assessed and correlated with survival.

Overall, oncogenic SGAs were detected in 51% of patients, with the highest incidence in myxoid liposarcoma (MLS, 88%). Patients with oncogenic SGA had a higher TMB and were associated with distant metastasis and/or progression-free survival (PFS) in ES, SFT, SS, and MLS in the localized group. TP53 mutations were the most common oncogenic SGAs across histotypes, with SFT and ES showing the highest rate (26% and 11%) and associated with worse PFS and disease-specific survival (P < .01). TP53 mutations in ES (P < .01) and SFT (P = .045) and TERT promoter mutations in SFT (P < .001) and MLS (P = .049) correlated with metastasis in the localized group.

Overall, oncogenic SGA correlated with a worse survival in certain TAS types.